Abstract：
The role of YTHDF2 in gastric cancer (GC) is controversial. Due to the limitations of technical difficulty and experimental period, research on completely knocking out YTHDF2 is rare. Therefore, further investigations are still needed to clarify the YTHDF2\'s clinical significance and biological function in GC. To carry out the investigation, an analysis was performed on the expression levels of YTHDF2 in both publicly available databases and samples obtained from patients with gastric cancer. Based on the complete knockout of YTHDF2 using the CRISPR-Cas9 system, in vivo and in vitro experiments were conducted to analyze the effects of YTHDF2 on tumor formation, radiotherapy and chemoradiotherapy resistance in GC. Our investigation revealed an increase in YTHDF2 levels in GC tissues, which was found to be associated with a negative prognosis. Under hypoxic conditions, high expression of YTHDF2 enhanced the invasion of gastric cancer cells, and high expression of YTHDF2 was associated with HIF-1a. YTHDF2 facilitated gastric cancer cell growth in vitro and in vivo. Moreover, the results of the present study demonstrated that YTHDF2 mediated the expression of CyclinD1 and stability of CyclinD1 mRNA. CyclinD1 knockdown inhibited YTHDF2-mediated GC cell proliferation whereas CyclinD1 overexpression ameliorated YTHDF2 knockdown-induced inhibition of GC progression. Furthermore, YTHDF2 also promoted resistance to DDP and CTX chemotherapy, along with radiotherapy treatment for GC cells. The findings suggested that YTHDF2 expression accelerated GC progression through a potential mechanism involving CyclinD1 expression, and enhanced chemoradiotherapy resistance. This indicated that YTHDF2 could be a promising prognostic biomarker and therapeutic target for individuals diagnosed with GC.
摘要：
YTHDF2在胃癌（GC）中的作用是有争议的。由于技术难度和实验周期的限制,完全敲除YTHDF2的研究很少。因此,YTHDF2在GC中的临床意义和生物学功能仍需进一步研究。为了进行调查，我们对公开数据库和胃癌患者样本中YTHDF2的表达水平进行了分析.基于使用CRISPR-Cas9系统完全敲除YTHDF2，进行了体内和体外实验，以分析YTHDF2对肿瘤形成的影响，GC的放疗和放化疗抵抗。我们的调查显示GC组织中YTHDF2水平增加，这被发现与阴性预后有关。在缺氧条件下,YTHDF2的高表达增强了胃癌细胞的侵袭能力,YTHDF2的高表达与HIF-1a相关。YTHDF2在体外和体内促进胃癌细胞生长。此外，本研究结果表明，YTHDF2介导了CyclinD1的表达和CyclinD1mRNA的稳定性。CyclinD1敲低抑制了YTHDF2介导的GC细胞增殖，而CyclinD1过表达改善了YTHDF2敲低诱导的GC进展抑制。此外，YTHDF2还促进了对DDP和CTX化疗的耐药性，以及对GC细胞的放射治疗。研究结果表明，YTHDF2表达通过涉及CyclinD1表达的潜在机制加速GC进展，增强了对放化疗的抵抗力。这表明YTHDF2可能是诊断患有GC的个体的有希望的预后生物标志物和治疗靶标。
